Potassium ions can cross both the outer and inner mitochondrial membranes by means of multiple routes. A few potassium-permeable ion channels exist in the outer membrane, while in the inner membrane, a multitude of different potassium-selective and potassium-permeable channels mediate K⁺ uptake into energized mitochondria. In contrast, potassium is exported from the matrix thanks to an H⁺/K⁺ exchanger whose molecular identity is still debated. Among the K⁺ channels of the inner mitochondrial membrane, the most widely studied is the ATP-dependent potassium channel, whose pharmacological activation protects cells against ischemic damage and neuronal injury. In this review, we briefly summarize and compare the different hypotheses regarding the molecular identity of this patho-physiologically relevant channel, taking into account the electrophysiological characteristics of the proposed components. In addition, we discuss the characteristics of the other channels sharing localization to both the plasma membrane and mitochondria.

Alzheimer's disease (AD) is a tauopathy characterized by the deposition of amyloid aggregates of hyperphosphorylated Tau protein and amyloid-(3 peptide (A(3) in the brain. Nevertheless, a soluble, oligomeric forms of Tau and A(3 are considered to be the most neurotoxic species responsible for neurodegenerative processes in AD. The mechanism of action of these oligomers remains largely unclear. Previously, we demonstrated the inhibition of the large-conductance calcium-activated potassium channel (BKCa) by A(3. Therefore, in the present study we investigated the effect of Tau protein on the BKCa activity. Furthermore, since prion protein (PrP) interacts with Tau and the N-terminal fragment of PrP, called N1, can be neuroprotective in tauopathies, we checked whether N1 can also act at the level of BKCa channel. In the studies we used monomers, oligomers and amyloid fibrils of aggregation-prone Tau fragment, called K18, carrying tauopathy-associated mutation - deletion of Lys280 (K18 Delta 280). Additionally, to induce formation of neurotoxic oligomers, K18 Delta 280 was phosphorylated by protein kinase A (PKA). The activity of the plasma membrane BKCa of hippocampal neurons was recorded using single-channel patch-clamp technique in both inside-out and outside-out modes, exposing the cytosolic or extracellular surface of the membrane, respectively. In the outside-out mode - performing the extracellular application of the neurotoxic oligomers of phosphorylated K18 Delta 280, we observed a significant and concentration-dependent decrease in the probability of opening (Po) of BKCa. The Po of BKCa was fully recovered after washing the oligomers out. In the case of the inside-out patch-clamp configuration, we found that the Po of BKCa was not affected by the oligomers. In contrast to the oligomers, the monomers and amyloid fibrils of K18 Delta 280 had no effect on the channel activity, analyzed in inside-out as well as outside-out modes. Noteworthy, upon incubation with N1, the oligomers did not inhibit BKCa channel. The BKCa channel inhibition, dependent on the outside-out membrane orientation, implies specific interaction of the oligomers with the extracellular part of the channel. Moreover, our results suggest that N1 can convert the neurotoxic oligomers of Tau into a form which is not able to inhibit the channel, and indicate novel possible neuroprotective mechanism of PrP action in AD and other tauopathies.